The overall objective of this Center of Excellence for Research on Complementary and Alternative Medicine in Alzheimer's disease application is to identify bioactive grape-derived polyhenols in AD prevention and/or therapy in the Tg2576 mouse model of Alzheimer's disease-type Ap neuropathology and cognitive deterioration. The proposed studies in this application are based on our hypothesize that selective bioactive grape-derived polyphenols protects against the onset and progression of AD-type cognitive deterioration by inhibiting the generation of A/7peptides from the amyloid precursor protein. We will test this hypothesis by using bio-guided fractionation methodologies to generate polyphenol preparations with progressively less complexity from Cabernet Sauvignon and from Concord purple grape juice that will exert A0- lowering activity in the Tg2576 AD mouse model. We will continue to explore the efficacy of ApMowering polyphenol preparations to attenuate the onset and progression of AD-type cognitive deterioration in Tg2576 mice and to clarify the mechanisms of action. The proposed studies in this application will complement the other Research Projects in this Center application and elucidate general mechanisms by which grape-derived polyphenolics may blunt age-related Alzheimer's disease, especially in a growing population affected by mild cognitive impairment that is at high risk for AD. Outcomes of the proposed studies will likely result in the development of selective grape-derived polyphenolic compounds as lead compounds for clinical testing in Alzheimer's disease